阅读说明：本技术 光稳定性及溶出性优异的药物制剂 (Pharmaceutical preparation having excellent photostability and dissolution property ) 是由 林尚美 五味真人 相川昇平 于 2018-11-15 设计创作，主要内容包括：本发明提供一种制剂,其为：在含有式(I)表示的化合物、其盐或其结晶的制剂中以光稳定化物质及聚合物进行包覆,尤其是以氧化钛、滑石中的1种以上作为光稳定化物质,以羟丙基甲基纤维素作为聚合物进行包覆,由此即使经光照射也几乎不着色。(The invention provides a preparation, which is: a preparation containing a compound represented by the formula (I), a salt thereof or a crystal thereof is coated with a light-stabilizing substance and a polymer, and particularly, coated with 1 or more of titanium oxide and talc as the light-stabilizing substance and hydroxypropyl methylcellulose as the polymer, so that the preparation is hardly colored even when irradiated with light.)

1. A solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has a coating layer comprising a light-stabilizing substance and a polymer,

2. the solid preparation according to claim 1, wherein the light-stabilizing substance in the coating layer is at least 1 selected from the group consisting of an edible tar pigment, an edible laked tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc.

3. The solid preparation according to claim 1, wherein the light-stabilizing substance in the coating layer is 1 or more selected from the group consisting of edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible cyan No. 1, edible cyan No. 2, edible red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, sodium chlorophyllin copper salt, copper chlorophyllin, red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, titanium oxide and talc.

4. The solid preparation according to claim 3, wherein the light-stabilizing substance in the coating layer is 1 or more selected from the group consisting of red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, titanium oxide and talc.

5. The solid preparation according to claim 4, wherein the light-stabilizing substance in the coating layer is titanium oxide and/or talc.

6. A solid preparation comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a coating layer comprising 1 or more polymers selected from the group consisting of edible Red No. 2, edible Red No. 3, edible Red No. 102, edible Red No. 104, edible Red No. 105, edible Red No. 106, edible yellow No. 4, edible yellow No. 5, edible Green No. 3, edible cyan No. 1, edible cyan No. 2, edible Red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, copper chlorophyllin sodium salt, copper chlorophyllin, red iron oxide, iron oxide yellow, iron oxide black, yellow iron oxide, titanium oxide and talc,

7. the solid preparation according to claim 6, which has a coating layer comprising titanium oxide and/or talc and a polymer and contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

8. The solid preparation according to any one of claims 1 to 7, wherein the polymer in the coating layer is 1 or more selected from the group consisting of a cellulose-based polymer, an acrylic-based polymer and a vinyl-based polymer.

9. The solid preparation according to any one of claims 1 to 7, wherein the polymer in the coating layer is at least 1 cellulose-based polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and ethylcellulose.

10. The solid preparation according to claim 9, wherein the cellulose-based polymer is hydroxypropylmethyl cellulose.

11. The solid preparation according to any one of claims 1 to 7, wherein the polymer in the coating layer is 1 or more acrylic polymers selected from methacrylic acid copolymers, aminoalkyl methacrylate copolymers E and aminoalkyl methacrylate copolymers RS.

12. The solid preparation according to any one of claims 1 to 7, wherein the polymer in the coating layer is at least 1 ethylene polymer selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and a polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer.

13. The solid preparation according to claim 12, wherein the vinyl polymer is polyvinyl alcohol.

14. A solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has a coating layer comprising titanium oxide and/or talc and hydroxypropylmethylcellulose,

15. the solid preparation according to any one of claims 1 to 14, which further contains a disintegrant.

16. A solid preparation comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a disintegrant,

17. the solid preparation according to claim 15 or 16, wherein the disintegrant is at least 1 selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, partially gelatinized starch, and sodium carboxymethyl starch.

18. The solid preparation according to claim 17, wherein the disintegrant is low-substituted hydroxypropyl cellulose or croscarmellose sodium.

19. The solid preparation according to claim 18, wherein the disintegrant is croscarmellose sodium.

20. The solid preparation according to claim 19, wherein the light-stabilizing substance in the coating layer is titanium oxide and/or talc, and the polymer is hydroxypropylmethylcellulose.

21. The solid preparation according to any one of claims 1 to 20, wherein the color difference Δ Ε of the solid preparation is 13 or less when 120 kallux-hr of light is irradiated.

22. A solid preparation comprising a light-stabilizing substance and a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

when the solid preparation is irradiated with 120 kallux hr light, the color difference Delta E is 13 or less.

23. The solid preparation according to claim 22, wherein the light-stabilizing substance is 1 or more selected from the group consisting of an edible tar pigment, an edible laked tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc.

24. The solid preparation according to claim 23, wherein the light-stabilizing substance is titanium oxide and/or talc.

25. The solid formulation according to any one of claims 1 to 24, in the form of a package of aluminum foil blisters.

26. A solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which is in a packaging form of an aluminum foil blister,

27. the solid formulation according to any one of claims 1 to 26, wherein the solid formulation is a granule or a tablet.

28. The solid preparation according to any one of claims 1 to 27, wherein the dissolution rate of the compound represented by formula (I) 45 minutes after the start of the dissolution test is 80% or more.

29. A method for analyzing a decomposition product in a solid preparation containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

a) a step of subjecting a sample to chromatography using a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

b) a step of obtaining data on the content or content ratio of the compound represented by the formula (II) in the chromatogram data obtained in the above-mentioned step

30. A decomposition composition of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

which contains a compound represented by the formula (II)

31. The solid preparation according to any one of claims 1 to 28, which contains 10mg, 20mg, 40mg or 80mg of the compound represented by formula (I)

32. A solid formulation according to any one of claims 1 to 28 for use in shortening the period of influenza development.

33. A solid formulation according to any one of claims 1 to 28 for use in reducing influenza virus.

[ technical field ] A method for producing a semiconductor device

The present invention relates to a preparation containing a polycyclic pyridone compound. The present invention relates to a solid preparation containing a polycyclic pyridone compound, which is coated with a light-stabilizing substance and a polymer and is not colored even by light irradiation, and more particularly, to a solid preparation containing a polycyclic pyridone compound, which contains 1 or more kinds of substances selected from the group consisting of an edible tar pigment, an edible laked tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc as a light-stabilizing substance, and which contains hydroxypropylmethylcellulose as a polymer and is not colored even by light irradiation.

[ Prior Art ] A method for producing a semiconductor device

Influenza is an acute respiratory infection caused by influenza virus infection. Millions of influenza-like patients are reported in japan in each winter, with high morbidity and mortality associated with influenza. The high risk group such as infants, the elderly is particularly important diseases, the complication rate of pneumonia is high in the elderly, and the elderly who die due to influenza are the majority.

As anti-influenza drugs, euphorbia (Symmetrel; trade name: Amantadine) or fumagiline (Flumadine; trade name: Rimantadine) which inhibit the virus enucleation/release from cells, Oseltamivir (Oseltamivir; trade name: clarithrone (Tamiflu)) which is a neuraminidase inhibitor, or Zanamivir (Zanamivir; trade name: Relenza (Relenza)) which inhibits the virus budding/release from cells, are known. However, there are problems of the appearance of resistant strains or side effects, and a fear of a pandemic of a novel influenza virus having a high pathogenicity or lethality, and therefore, development of an anti-influenza drug having a novel mechanism of action is expected.

Since a CAP structure (CAP) -dependent endonuclease that is an enzyme derived from influenza virus is necessary for virus propagation and has virus-specific enzyme activity that is not possessed by the host, it is considered to be a target for an anti-influenza drug.

As a compound that inhibits CAP structure (CAP) -dependent endonuclease, patent document 1 describes that a compound represented by the following formula (II) can be used as a compound having an antiviral action, particularly an activity of inhibiting the proliferation of influenza virus.

In the case of in vivo administration (for example, oral administration) of the compound represented by the formula (II), it is necessary to provide a compound which is efficiently absorbed in the body to exhibit a high pharmacological effect and which shortens the period of influenza, and in order to achieve the above object, a compound represented by the formula (I) which is a prodrug of the compound represented by the formula (II) is provided. A compound represented by formula (I) is also disclosed in patent document 1.

However, patent document 1 does not disclose a specific preparation of the compound represented by formula (I).

Preparations having improved dissolution properties are disclosed in patent documents 5 to 7. However, the chemical structures of the compounds used in patent documents 5 to 7 and the compounds represented by formula (I) are greatly different, and it is not known, nor disclosed or suggested, whether or not the elution property of the compounds represented by formula (I) can be improved by the formulation described in patent documents 5 to 7. Further, it is also possible to produce a large amount of the similar substance by the additive for improving the elution property.

Patent documents 2 to 4 describe that coloring of a preparation colored by light irradiation can be reduced by coating the preparation with titanium oxide. However, whether or not the preparation is colored by light irradiation varies depending on the compound, and it is not clear whether or not the preparation containing the compound represented by the formula (I) is colored, and there is no disclosure or suggestion.

[ Prior art documents ]

[ patent document ]

[ patent document 1] International publication No. 2016/175224 Specification

[ patent document 2] Japanese patent laid-open publication No. 2013-14610

[ patent document 3] International publication No. 2002/060446 Specification

[ patent document 4] International publication No. 2007/052592 Specification

[ patent document 5] Japanese patent application laid-open No. 2010-270112

[ patent document 6] International publication No. 2004/052342 Specification

[ patent document 7] International publication No. 2012/144592 Specification

[ summary of the invention ]

[ problems to be solved by the invention ]

The present invention addresses the problem of finding a preparation containing a compound represented by formula (I) that does not stain even when irradiated with light, and providing a preparation having improved elution properties of the compound represented by formula (I) from the preparation.

[ means for solving problems ]

The present inventors have found that when a preparation containing a compound represented by the formula (I) is irradiated with light, the preparation itself is colored. Further, it was found that the compound represented by the formula (I) had low solubility and had difficulty in obtaining desired elution properties.

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found that when a light-stabilizing substance and a polymer are coated on a preparation containing a compound represented by formula (I), the preparation is hardly colored even when irradiated with light, and thus the present invention has been completed. Further, the compound represented by the formula (I) has low solubility and has difficulty in obtaining a desired dissolution property, and various disintegrants have been studied to find a disintegrant which is less in the like and can improve the dissolution property, and thus the present invention has been completed. Hereinafter, the preparation completed in the present invention may be referred to as "the present preparation".

That is, the present invention relates to

(1) A solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

which has a coating layer containing a light-stabilizing substance and a polymer,

(2) the solid preparation according to the above (1), wherein the light-stabilizing substance in the coating layer is at least 1 selected from the group consisting of an edible tar pigment, an edible laked tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc,

(3) the solid preparation according to the above (1), wherein the light-stabilizing substance in the coating layer is at least 1 selected from the group consisting of edible Red No. 2, edible Red No. 3, edible Red No. 102, edible Red No. 104, edible Red No. 105, edible Red No. 106, edible yellow No. 4, edible yellow No. 5, edible Green No. 3, edible cyan No. 1, edible cyan No. 2, edible Red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, sodium chlorophyllin copper salt, copper chlorophyllin, red iron oxide (Japanese: バンガラ), iron oxide red, iron oxide yellow, iron oxide black, yellow iron oxide, titanium oxide and talc,

(4) the solid preparation according to item (3) above, wherein the light-stabilizing substance in the coating layer is at least 1 selected from the group consisting of red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, titanium oxide and talc,

(5) the solid preparation according to the above (4), wherein the light-stabilizing substance in the coating layer is titanium oxide and/or talc,

(6) a solid preparation comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a coating layer comprising 1 or more polymers selected from the group consisting of edible Red No. 2, edible Red No. 3, edible Red No. 102, edible Red No. 104, edible Red No. 105, edible Red No. 106, edible yellow No. 4, edible yellow No. 5, edible Green No. 3, edible cyan No. 1, edible cyan No. 2, edible Red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, copper chlorophyllin sodium salt, copper chlorophyllin, red iron oxide, iron oxide yellow, iron oxide black, yellow iron oxide, titanium oxide and talc,

(7) the solid preparation containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to the above (6), wherein the solid preparation has a coating layer containing titanium oxide and/or talc and a polymer,

(8) the solid preparation according to any one of the above (1) to (7), wherein the polymer in the coating layer is at least 1 selected from the group consisting of a cellulose-based polymer, an acrylic polymer and a vinyl polymer,

(9) the solid preparation according to any one of (1) to (7) above, wherein the polymer in the coating layer is at least one cellulose-based polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and ethylcellulose,

(10) the solid preparation according to (9) above, wherein the cellulose-based polymer is hydroxypropylmethylcellulose,

(11) the solid preparation according to any one of the above (1) to (7), wherein the polymer in the coating layer is at least 1 acrylic polymer selected from the group consisting of a methacrylic acid copolymer, an aminoalkyl methacrylate copolymer E and an aminoalkyl methacrylate copolymer RS,

(12) the solid preparation according to any one of the above (1) to (7), wherein the polymer in the coating layer is at least one vinyl polymer selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and a polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer,

(13) the solid preparation according to (12) above, wherein the vinyl polymer is polyvinyl alcohol,

(14) a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has a coating layer comprising titanium oxide and/or talc and hydroxypropylmethylcellulose,

(15) the solid preparation according to any one of the above (1) to (14), which further contains a disintegrant,

(16) a solid preparation comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a disintegrant,

(17) the solid preparation according to the above (15) or (16), wherein the disintegrant is at least 1 selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, partially gelatinized starch and sodium carboxymethyl starch,

(18) the solid preparation according to (17) above, wherein the disintegrant is low-substituted hydroxypropylcellulose or croscarmellose sodium,

(19) the solid preparation according to (18) above, wherein the disintegrant is croscarmellose sodium,

(20) the solid preparation according to (19) above, wherein the light-stabilizing substance in the coating layer is titanium oxide and/or talc, the polymer is hydroxypropylmethylcellulose,

(21) the solid preparation according to any one of the above (1) to (20), wherein the color difference Δ E is 13 or less when the solid preparation is irradiated with 120 kallux hr of light,

(22) a solid preparation comprising a light-stabilizing substance and a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

when 120 kallux hr of light is irradiated, the color difference Delta E is 13 or less,

(23) the solid preparation according to item (22), wherein the light-stabilizing substance is at least 1 selected from the group consisting of an edible tar pigment, an edible laked tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc,

(24) the solid preparation according to (23) above, wherein the light-stabilizing substance is titanium oxide and/or talc,

(25) the solid preparation according to any one of the above (1) to (24), which is in a form of a package of a blister of aluminum foil,

(26) a solid preparation in the form of a blister pack of aluminum foil and containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

(27) the solid preparation according to any one of the above (1) to (26), wherein the solid preparation is a granule or a tablet,

(28) the solid preparation according to any one of the above (1) to (27), wherein the dissolution rate of the compound represented by the formula (I) is 80% or more 45 minutes after the start of the dissolution test,

(29) a method for analyzing a decomposition product in a solid preparation containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

a) a step of subjecting a sample to chromatography using a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

formula (I):

and

b) a step of obtaining data on the content or content ratio of the compound represented by the formula (II) in the chromatogram data obtained in the above-mentioned step,

formula (II):

(30) a decomposition composition of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which contains a compound represented by the formula (II),

formula (II):

formula (I):

(31) the solid preparation according to any one of the above (1) to (28), which contains 10mg, 20mg, 40mg or 80mg of the compound represented by the formula (I),

(32) the solid preparation according to any one of the above (1) to (28) and (31), which is used for shortening the period of influenza development,

(33) the solid preparation according to any one of (1) to (28) and (31) above, which is used for reducing influenza virus.

[ Effect of the invention ]

According to the present invention, in a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof having a coating layer comprising a light-stabilizing substance and a polymer, the color of the preparation hardly changes from the initial stage of the test even when irradiated with light. That is, the formulation of the present invention preferably has a color difference Δ E of 13 or less.

[ description of the drawings ]

Fig. 1 is a graph showing the dissolution behavior of a tablet using low-substituted hydroxypropylcellulose as a disintegrant.

Fig. 2 is a graph showing the dissolution behavior of a tablet using croscarmellose sodium as a disintegrant.

[ embodiments of the invention ]

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used as an active ingredient in the preparation of the present invention

A process for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is disclosed in patent document 1.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is converted in vivo into a compound represented by the formula (II), and has a CAP structure (CAP) -dependent endonuclease inhibitory action. Therefore, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be used as a therapeutic and/or prophylactic agent for influenza.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be used for symptoms and/or diseases induced by influenza virus. For example, the treatment and/or prevention of cold symptoms accompanied by fever, chills, headache, myalgia, general malaise, etc., tracheitis symptoms such as sore throat, runny nose, nasal obstruction, cough, sputum, etc., gastrointestinal symptoms such as abdominal pain, vomiting, diarrhea, etc., and furthermore, complications accompanying secondary infection such as acute encephalopathy, pneumonia, etc., and the improvement of symptoms. That is, the compounds used in the present invention are useful for the treatment and/or prevention of influenza virus infections.

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is effective for shortening the period of an influenza disease. For example, the duration of influenza can be shortened by about 20 to 40 hours, about 25 to 30 hours. In particular, the "cough", "sore throat", "headache", "nasal congestion", "mild fever or chills", "muscle or joint pain", "fatigue" can be reduced until the time to obtain an improvement. It is particularly beneficial to shorten the time to "nasal congestion", "muscle or joint pain", "fatigue", "mild fever or chills", "headache" to obtain improvement. It is more beneficial to shorten the time to "nasal congestion" and "muscle or joint pain" to achieve improvement.

Further, the compound (parent compound and/or prodrug) used in the present invention can be a superior drug useful for the treatment and/or prevention of influenza virus infection because it can reduce influenza virus in vivo in a short period of time. The effect of reducing the amount of influenza virus in vivo is observed within 72 hours, preferably within 48 hours, more preferably within 24 hours after administration of the compound used in the present invention, and a therapeutic effect at an earlier stage can be expected as compared with other drugs.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has utility as a pharmaceutical. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is a prodrug, and has the advantages of high oral absorbability, good bioavailability and clearance, high lung migration performance and the like, so that the compound can be used as an excellent medicine.

The compound represented by the formula (I) or the pharmaceutically acceptable salt thereof has high metabolic stability or oral absorbability, and shows good bioavailability and clearance rate. In addition, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has high pulmonary migration property and a long half-life. Further, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has advantages of high non-protein binding rate, low hERG channel inhibition or CYP inhibition, confirmation of CPE (CytoPathic Effect, cell degeneration) inhibitory Effect, and/or negative in phototoxicity test, Ames test, genotoxicity test, no toxicity such as liver damage, and the like. Therefore, the pharmaceutical composition of the present invention can be used as an excellent pharmaceutical product.

The amount of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof to be administered varies depending on the administration method, age, weight, condition of a patient and kind of the disease, and in general, when orally administered, about 0.05mg to 3000mg, preferably about 0.1mg to 1000mg, more preferably about 10mg to 80mg, most preferably about 10mg to 40mg is administered daily to an adult, and may be administered in divided portions as necessary. In non-oral administration, about 0.01mg to 1000mg, preferably about 0.05mg to 500mg, about 1mg to 80mg per day is administered to an adult. It can be administered 1 time a day or in several divided doses.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other agents or the like (hereinafter, simply referred to as concomitant agents) for the purpose of enhancing the action of the compound or reducing the administration amount of the compound. For example, diseases in influenza can be used in combination with neuraminidase inhibitors (e.g., oseltamivir, zanamivir, Peramivir (Peramivir), and canavir (Inavir)), RNA-related RNA polymerase inhibitors (e.g., Favipiravir (Favipiravir)), M2 protein inhibitors (e.g., amantadine), PB2Cap binding inhibitors (e.g., VX-787), anti-HA antibodies (e.g., MHAA4549A), or immune agents (e.g., Nitazoxanide). In this case, the timing of administration of the compound and the concomitant agent used in the present invention is not particularly limited, and administration to a subject may be performed simultaneously or with a time difference. Further, the combined agent with the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be administered as 2 or more preparations containing each active ingredient, or may be administered as a single preparation containing all the active ingredients.

The administration amount of the concomitant drug can be appropriately selected based on the amount used clinically. The formulation ratio of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof to the concomitant agent can be appropriately selected depending on the administration subject, the administration route, the disease, symptom, combination, and the like of the subject. For example, when the administration to a subject is a human, a combined agent of 0.01 to 100 parts by weight may be used for 1 part by weight of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a high inhibitory activity against cap-structure-dependent endonucleases, and can be a drug with reduced side effects due to the effects of a virus-specific enzyme, high selectivity, and the like.

Hereinafter, a method for specifying the compound represented by the formula (I), the crystal thereof, or the compound represented by the formula (II) will be described.

Unless otherwise indicated, all numbers recited in the specification and claims are to be understood as being approximate. The variation in the numerical value is caused by device calibration, device errors, purity of a substance, crystal size, sample size, and other factors.

The term "crystal" as used herein means that atoms, ions, molecules, and the like constituting a solid have a regular and correct arrangement structure, and as a result, have a periodic and anisotropic structure. The degree of crystallization of the crystal form can be measured by various techniques including, for example, powder X-ray diffraction measurement, dynamic moisture adsorption measurement, differential scanning calorimetry measurement, differential thermogravimetry simultaneous measurement, solution colorimetry measurement, and dissolution characteristics.

NMR analysis of the Compound at 300MH_ZBy using DMSO-d₆、CDCl₃And (4) measuring.

Determination of powder X-ray diffraction model

The crystals obtained in the respective examples were subjected to powder X-ray diffraction measurement in accordance with the powder X-ray diffraction measurement method described in the general test method of the japanese pharmacopoeia. The measurement conditions are as follows.

(device)

MiniFlex600 or RINT-TTRIII manufactured by Rigaku corporation

(method of operation)

A detector: high speed one-dimensional detector (D/Tecultra2) and variable knife-edge effect

The determination method comprises the following steps: reflection method

The kind of light source: cu tube ball

The wavelength used was: CuK alpha line

Tube current: 10mA or 15mA

Tube voltage: 30Kv or 40Kv

A sample plate: aluminium or glass

Incident angle (θ) of X-ray: 3-40 °, sampling width: 0.01 °, or

Incident angle (θ) of X-ray: 4-40 °, sampling width: 0.02 degree

In general, the diffraction angle (2 θ) in the powder X-ray diffraction causes an error in the range of. + -. 0.2. degree, and therefore, the value of the diffraction angle also includes a value in the range of. + -. 0.2. degree. Therefore, not only crystals in which the diffraction angles of the peaks in the powder X-ray diffraction are completely uniform but also crystals in which the diffraction angles of the peaks are uniform with an error of about ± 0.2 ° are included in the present invention.

The amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to be formulated in the present preparation is 1 to 80% by weight, preferably 5 to 75% by weight, more preferably 10 to 70% by weight, with respect to the total amount of the preparation.

The formulations of the present invention contain a light-stabilizing substance. In the present specification, as the light-stabilizing substance, any additive that can stabilize the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof against light and can prevent discoloration of the formulation may be used, and those contained in japanese pharmacopoeia, pharmaceutical standards outside japanese pharmacopoeia, pharmaceutical additive standards, and food additive official books can be used.

The light stabilizing substance is a light shielding substance having a light shielding effect of shielding light or a light absorbing substance having a light absorbing effect. Specific examples thereof include edible tar pigments, edible colored tar pigments, edible natural pigments, iron oxide, titanium oxide, talc, and the like. Preferred examples thereof include edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible cyan No. 1, edible cyan No. 2, edible red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, sodium copper chlorophyllin, red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, titanium oxide, talc, and the like. More preferred examples include titanium oxide and talc as light-shielding substances; red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide as light-absorbing substances; titanium oxide and talc are most preferable as the light-shielding substance.

The light-stabilizing substance of the preparation of the present invention may be formulated in the preparation or may coat the surface of the preparation, and preferably the light-stabilizing substance is contained in a so-called coating layer which coats the surface of the preparation. When a light-stabilizing substance is contained in the coating layer of the formulation, light from the outside of the formulation can be absorbed and shielded, and the light stability of the compound represented by formula (I) contained in the formulation can be improved or the formulation can be prevented from being discolored.

The content of the light-stabilizing substance in the preparation of the present invention may be an amount at which the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is stabilized against light. Specifically, the surface area of a light-shielding substance such as titanium oxide or talc, which shields light, in the light-stabilizing substance to the preparation is 1mm²From 0.00075 to 0.075mg, preferably from 0.001 to 0.05mg, more preferably from 0.0015 to 0.03 mg.

The formulations of the present invention contain a polymer. In the present specification, the polymer may be used as it is stored in japanese pharmacopoeia, pharmaceutical specifications outside japanese pharmacopoeia, pharmaceutical additive specifications, and food additive official books. Specific examples thereof include cellulose polymers such as hydroxypropylmethylcellulose (hydroxypropyl methylcellulose), polyvinyl alcohol, ethyl cellulose, carboxymethylethylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, fumaric acid/stearic acid/polyvinyl acetal diethylaminoacetate/hydroxypropyl methylcellulose mixture, acrylic polymers such as ethyl acrylate/methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methacrylate/methacrylic acid copolymer, dried methacrylic acid copolymer, dimethylaminoethyl methacrylate/methyl methacrylate copolymer and the like, polyvinyl pyrrolidone, crospovidone, a carboxyvinyl polymer, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer, polyvinyl alcohol copolymer and other vinyl polymers, carnauba wax, stearyl alcohol, shellac, cetyl alcohol and the like, and hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose) is preferred.

The polymer of the preparation of the present invention may be blended in the preparation, or may be used as a so-called coating agent for coating the surface of the preparation, preferably for forming a coating layer by coating the surface of the preparation. If the coating layer of the formulation contains a polymer, the surface of the formulation can be coated with a light-stabilizing substance at the same time, and the light stability of the compound represented by formula (I) contained in the formulation can be improved or the formulation can be prevented from being discolored.

The polymer content in the coating layer in the present specification may be an amount that can coat the surface of the formulation with the light-stabilizing substance.

The formulations of the present invention may also contain a disintegrant. The disintegrant used may be one contained in japanese pharmacopoeia, pharmaceutical standards outside japanese pharmacopoeia, pharmaceutical additive standards, food additive official books, and the like, and the amount of the analogous substance including the compound represented by formula (II) may be increased depending on the type of the disintegrant. Specifically, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like are included, and croscarmellose sodium is preferred.

The content of the disintegrant in the formulation of the present invention is 0.5 to 20% by weight, preferably 0.75 to 15% by weight, more preferably 1 to 10% by weight, with respect to the total amount of the formulation. If the amount is less than this, the solid preparation, particularly the tablet, may not be sufficiently disintegrated.

The formulations of the invention may also contain excipients. The excipient may be one contained in the japanese pharmacopoeia, the pharmaceutical specifications outside the japanese pharmacopoeia, the specifications of pharmaceutical additives, and the food additive official books. Specific examples thereof include sugar alcohols such as D-mannitol, xylitol, sorbitol, maltitol, lactitol and oligosaccharide, saccharides such as xylose, glucose (glucose), fructose (fructose), maltose (maltose), lactose (lactose), sucrose (sucrose), isomerized sugar, germinated syrup, refined white sugar, refined white sugar spherical particles, anhydrous lactose and white sugar/starch spherical particles, saccharides such as hemi-digestible starch, glucose hydrate, powdered sugar, crystalline cellulose, microcrystalline cellulose, pullulan (pullulan), beta-cyclodextrin, taurine, powdered sugar, sodium chloride, citric acid, sodium citrate, glycine, calcium gluconate, L-glutamic acid, tartaric acid, potassium hydrogen tartrate, ammonium carbonate, dextran 40, dextrin, calcium lactate, povidone, polyethylene glycol (polyethylene glycol) 1500, polyethylene glycol 1540, calcium gluconate, calcium tartrate, calcium carbonate, calcium lactate, polyethylene glycol (polyethylene glycol) 1540, Polyethylene glycol 4000, polyethylene glycol 6000, citric anhydride, DL-malic acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, L-aspartic acid, alginic acid, sodium carboxymethylcellulose, hydrated silicon dioxide, crospovidone, calcium glycerophosphate, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, wheat flour, wheat starch, wheat germ powder, wheat germ oil, rice flour, rice starch, cellulose acetate phthalate, titanium oxide, magnesium oxide, dihydroxyaluminum aminoacetate, tricalcium phosphate (tertiary calcium phosphate), talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, natural aluminum silicate, corn starch granules, potato starch, hydroxypropyl cellulose, hydroxypropyl starch, anhydrous calcium hydrogen phosphate granules, calcium dihydrogen phosphate and the like, preferably, the saccharide and crystalline cellulose are used, and more preferably, lactose and crystalline cellulose are used.

The content of excipients in the formulations of the invention is from 10 to 90% by weight, preferably from 15 to 87.5% by weight, more preferably from 20 to 85% by weight, based on the total amount of the formulation.

The formulations of the present invention may contain a binder. The binder used is a binder contained in japanese pharmacopoeia, pharmaceutical standards outside japanese pharmacopoeia, pharmaceutical additive standards, food additive official books, and the like. Specific examples thereof include hydroxypropyl cellulose, corn starch, gelatinized starch, partially gelatinized starch, gum arabic, acacia powder, gelatin, agar, dextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, crystalline cellulose, methyl cellulose, ethyl cellulose, carboxymethylethylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone is preferable.

The content of binder in the formulations of the invention is from 0.1 to 20% by weight, preferably from 0.25 to 15% by weight, more preferably from 0.5 to 10% by weight, based on the total amount of the formulation.

The formulations of the present invention may also contain a lubricant. The lubricant may be one contained in japanese pharmacopoeia, pharmaceutical specifications outside japanese pharmacopoeia, pharmaceutical additive specifications, food additive official books, and the like. Specific examples thereof include metal stearate, sucrose fatty acid ester, talc, hydrated silica, and sodium stearyl fumarate is preferable.

The amount of lubricant is generally from 0.05 to 10% by weight, preferably from 0.075 to 7.5% by weight, more preferably from 0.1 to 5% by weight, based on the total formulation.

In order to coat the polymer efficiently, the coating agent of the coating layer of the present invention may contain a plasticizer or an aggregation inhibitor, and those contained in the japanese pharmacopoeia, the pharmaceutical specifications outside the japanese pharmacopoeia, the pharmaceutical additive specifications, and the food additive official books may be used. Specific examples thereof include triethyl citrate, glycerin fatty acid esters, sucrose fatty acid esters, castor oil, triacetin, talc, and the like. On the other hand, polyethylene glycol (polyethylene glycol) may be blended, and the like may be added.

The preparation of the present invention may contain a pigment or a coloring agent, and a pigment contained in the japanese pharmacopoeia, the pharmaceutical specifications outside the japanese pharmacopoeia, the pharmaceutical additive specifications, or the like may be used. The pigment may be contained in the tablet or in the coating. Specific examples of the coloring matter include iron oxide, tar coloring matter, and natural coloring matter. The iron oxide includes red iron oxide, yellow iron oxide, black iron oxide, etc. The tar pigment includes edible yellow No. 4 aluminum lake, edible cyan No. 1 aluminum lake, edible red No. 3 aluminum lake, edible cyan No. 1, edible cyan No. 2, edible yellow No. 4, edible yellow No. 5, edible red No. 102, edible red No. 2, edible red No. 3, etc. The natural pigment includes Curcuma rhizome extract, beta-carotene, carotene solution, sodium copper chlorophyllin, powder of extract of leaf of naked barley, dry powder of green juice of naked barley, extract of leaf of naked barley, titanium oxide, and pulvis Talci. Pigments are also included in the light stabilizing material user.

The preparation of the present invention may contain other additives as necessary, and additives to be incorporated into the japanese pharmacopoeia, pharmaceutical specifications outside the japanese pharmacopoeia, pharmaceutical additive specifications, and food additive official books can be used. In addition, the content of the additive may be in any ratio. Specific examples of the additives other than the above include perfumes, fluidizing agents, and flavoring agents.

Specific examples of the flavor include orange flavor, mandarin oil, caramel, camphor, cassia oil, spearmint oil, strawberry flavor, chocolate flavor, cherry flavor, sweet orange essential oil, pine oil, peppermint oil, vanilla flavor, bitter flavor, fruit flavor, peppermint flavor, mixed flavor, peppermint flavor, menthol, lemon powder, lemon oil, rose oil, and the like.

Specific examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, talc, and the like.

Specific examples of the taste-modifying agent include aspartame, sucralose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and salts thereof, citric acid anhydride, L-glutamine and salts thereof, succinic acid and salts thereof, acetic acid, tartaric acid and salts thereof, sodium bicarbonate, fumaric acid and salts thereof, malic acid and salts thereof, glacial acetic acid, disodium inosinate, and honey.

The preparation of the present invention may be a solid preparation. Specifically, the agent may be any of granules, fine granules, tablets, powders, capsules, pills, and the like, and preferably granules or tablets. The weight of the compound represented by formula (I) contained in the solid preparation is not particularly limited, and specifically, 10mg, 20mg, 40mg, or 80mg is preferable. In this case, 10mg means in the range of 9.0 to 11.0mg, preferably in the range of 9.5 to 10.5mg, 20mg means in the range of 18.0 to 22.0mg, preferably in the range of 19.0 to 21.0mg, 40mg means in the range of 36.0 to 44.0mg, preferably in the range of 38.0 to 42.0mg, 80mg means in the range of 72.0 to 88.0mg, preferably in the range of 76.0 to 84.0 mg.

The method for producing granules in the preparation of the present invention is not particularly limited, and specifically, a method of mixing additives such as active ingredients, disintegrants, and excipients to produce a mixed powder and then granulating the mixed powder is preferable to be a wet granulation method or a compression molding method in which granulation is performed with water or a solvent containing a binder, and a dry granulation method or a melt granulation method in which water is not used. As a machine for mixing the active ingredients, additives, and the like, a V-type mixer or a container blender can be used. Further, as a machine for granulation, a wet extrusion granulator, a fluidized bed granulator, a stirring granulator, a dry crushing granulator, or a melt extrusion granulator can be used. In the case of wet granulation, the moisture content at the time of granulation is 1 to 50%, preferably 5 to 47.5%, more preferably 10 to 45% with respect to the mixed powder.

The method for producing a tablet in the preparation of the present invention is not particularly limited, and specifically, a tableting method may be employed in which granules are produced by the above-described method, and the granules are mixed with a disintegrant and a lubricant, and the mixed granules are tabletted with a tableting machine. As a machine for mixing the active ingredients, additives, and the like, a V-type mixer or a container blender can be used. In addition, the tablet press may use a single-punch press, a rotary press, or the like.

After the production of the above-mentioned granules or tablets, the granules or tablets of the present invention may be coated with a light-stabilizing material and a polymer to form a coating layer. When the granules are coated, a fluidized bed granulation coating machine, a fluidized bed rotary coating machine or the like may be used. When the tablet is coated, a pan coater, a vented coater or the like may be used. When a coating layer is formed on the surface of a preparation by a light-stabilizing substance and a polymer, the light-stabilizing substance and the polymer are dissolved or suspended in a solvent such as water or ethanol to prepare a coating solution. The coating solution is sprayed onto the granules or tablets while the granules or tablets are fluidized in a coating machine, and dried to form a coating layer.

The dissolution rate of the compound represented by formula (I) in the preparation of the present invention is 70% or more, preferably 75% or more, and more preferably 80% or more 45 minutes after the start of the dissolution test.

In the formulation of the present invention, even if irradiated with light, the similar substance hardly increases from the start of the experiment, and the color difference of the formulation hardly changes, particularly, the color difference Δ E of the formulation hardly changes from the start of the experiment. Specifically, when the formulation was placed in an exposure apparatus and irradiated with light of 120 kallux hr as the total irradiation light amount, the color difference of the formulation was Δ 13 or less.

Also, the present invention includes a method for analyzing a decomposition product in a solid preparation containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

a) a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used as a sample,

subjecting the sample to chromatography; and

b) a step of obtaining data on the content or content ratio of the compound represented by the formula (II) from the chromatographic data obtained in the above step

For example, the amount (content or content ratio) of a similar substance containing the compound represented by the formula (II) can be determined by high performance liquid chromatography. At this time, the compound represented by the formula (II) can be used as a reference for the measurement of the analogous substance. The content or content ratio of the compound represented by the formula (II) can be calculated from the peak area of the chromatogram data. For example, when the compound represented by the formula (I) or the compound represented by the formula (II) is measured by chromatography, a wavelength of 260nm can be used as the measurement wavelength. The content ratio may be a ratio to the whole preparation, a ratio to the compound represented by the formula (I), a ratio to the total of the compound represented by the formula (I) and the compound represented by the formula (II), or the like. Further, it is possible to reduce the color difference Δ E of the preparation by reducing the amount of the compound represented by formula (II).

In addition, formula (I)

The main analogs of the compounds represented are the following structures:

the content of the compound represented by the formula (I) in the solid preparation, particularly in the tablet, may be such that the content of the tablet can be made so that it is easy for a patient to take, and is 1 to 400mg, preferably 1.25 to 350mg, and more preferably 2.5 to 300mg per 1 tablet. Specifically, the content of the compound represented by the formula (I) per 1 tablet is 10mg, 20mg, 40mg or 80 mg. At this time, 10mg means in the range of 9.0 to 11.0mg, preferably in the range of 9.5 to 10.5mg, 20mg means in the range of 18.0 to 22.0mg, preferably in the range of 19.0 to 21.0mg, 40mg means in the range of 36.0 to 44.0mg, preferably in the range of 38.0 to 42.0mg, 80mg means in the range of 72.0 to 88.0mg, preferably in the range of 76.0 to 84.0 mg.

The solid preparation containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and a polymer.

A solid preparation using a substance that shields or absorbs light as a light stabilizing substance in the coating layer is preferable.

The light-stabilizing substance is preferably 1 or more light-stabilizing substances selected from the group consisting of edible tar pigments, edible laked tar pigments, edible natural pigments, iron oxide, titanium oxide and talc.

The light-stabilizing substance is preferably a light-absorbing substance such as edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible cyan No. 1, edible cyan No. 2, edible red No. 3 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible cyan No. 1 aluminum lake, edible cyan No. 2 aluminum lake, carmine, sodium copper chlorophyllin, red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, light-shielding substance such as titanium oxide, talc, silica, etc.

In particular, 1 or more selected from the group consisting of red iron oxide, yellow iron oxide, black iron oxide, yellow iron oxide, titanium oxide and talc are preferable.

Further preferred is titanium oxide and/or talc.

The polymer in the coating layer is preferably 1 or more selected from the group consisting of a cellulose polymer, an acrylic polymer and a vinyl polymer.

The cellulose-based polymer is preferably at least 1 selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and ethylcellulose.

Especially preferred is hydroxypropyl methylcellulose.

The acrylic polymer is preferably 1 or more selected from the group consisting of methacrylic acid copolymers, aminoalkyl methacrylate copolymers E and aminoalkyl methacrylate copolymers RS.

The vinyl polymer is preferably at least 1 selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, crospovidone, and polyvinyl alcohol-methyl methacrylate-acrylic acid copolymer.

The light-stabilizing substance in the coating layer is preferably titanium oxide or talc, and the polymer is preferably hydroxypropylmethylcellulose.

Preferred aspects are described below.

The solid preparation containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance which blocks or absorbs light and a polymer, and more preferably the solid preparation containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing titanium oxide, talc and a polymer.

On the other hand, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and 1 or more polymers selected from the group consisting of cellulosic polymers, acrylic polymers and vinyl polymers, preferably a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance which shields or absorbs light and 1 or more polymers selected from the group consisting of cellulosic polymers, acrylic polymers and vinyl polymers, and more preferably a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing 1 or more light-stabilizing substances selected from the group consisting of edible tar pigments, edible precipitated tar pigments, edible natural pigments, iron oxides, titanium oxides and talc and a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and a light-stabilizing substance selected from the group consisting of edible tar pigments, edible precipitated tar, The coating layer of 1 or more polymers selected from the group consisting of acrylic polymers and vinyl polymers, and particularly preferably, the solid preparation containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing titanium oxide, talc, and 1 or more polymers selected from the group consisting of cellulosic polymers, acrylic polymers, and vinyl polymers.

On the other hand, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and a cellulose-based polymer, preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and a cellulose-based polymer which shield or absorb light, more preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing 1 or more kinds of light-stabilizing substances and cellulose-based polymers selected from the group consisting of an edible tar pigment, an edible precipitated tar pigment, an edible natural pigment, iron oxide, titanium oxide and talc, and more preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing titanium oxide, titanium dioxide, and a cellulose-based polymer, Coating layers of talc and cellulose-based polymers.

On the other hand, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance and hydroxypropylmethylcellulose, preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing a light-stabilizing substance which shields or absorbs light and hydroxypropylmethylcellulose, more preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing 1 or more kinds of light-stabilizing substances selected from the group consisting of edible tar pigments, edible precipitated tar pigments, edible natural pigments, iron oxide, titanium oxide and talc and hydroxypropylmethylcellulose, more preferably, a solid preparation containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a coating layer containing titanium oxide, titanium dioxide, titanium, Talc and hydroxypropyl methylcellulose.

When the preparation of the present invention is packaged by a light absorber or a light shield, the color difference of the preparation is Δ 13 or less when 120 kallux hr of light is irradiated as the total irradiation light amount. Further, when a preparation containing only the compound represented by the formula (I) is packaged by a light absorber or a light shield, the color difference of the preparation is Δ 13 or less even when 120 kallux hr of light is irradiated as the total irradiation light amount. The light absorber or the light shield may be aluminum or a colored film, and the package form may be an aluminum foil blister.

The shape of the tablet may be any shape, and specifically, a tablet having a circular, oval, spherical, rod-like or doughnut-like shape may be used. Further, a multilayer sheet, a core sheet, or the like may be used, and a single layer ingot whose production method is simple is preferable. The cutting lines for marking and dividing the marks, characters, etc. which are beneficial to improving the identification can also be attached.

[ examples ]

The present invention will be described in detail below with reference to examples, comparative examples and reference examples, but the present invention is not limited to the above. Compound II can be produced by the method disclosed in International publication No. 2016/175224.